Guanidine complexes as fungicides



United States Patent 3,479,437 GUANIDINE COMPLEXES AS FUNGICIDES KarolySzabo, Syracuse, N.Y., and Ashley H. Freiberg,

Santa Clara, Calif., assignors to Stauifer Chemical Company, New York,N.Y., a corporation of Delaware No Drawing. Application Aug. 26, 1963,Ser. No. 304,607, new Patent No. 3,320,229, dated May 16, 1967, which isa continuation-in-part of abandoned application Ser. No. 191,432, May 1,1962. Divided and this application Mar. 24, 1967, Ser. No. 625,627

Int. Cl. A61k 9/20 US. Cl. 424-304 18 Claims ABSTRACT OF THE DISCLOSUREThe method of inhibiting the growth of fungi by applying thereto aneffective amount of a guanidine complex of a completely halogenatedacetone having the following I(6-; NH7C- and CN; NH

it being understood that the number of non-hydrocarbon R groups attachedto the same nitrogen atom does not exceed 1, X and X are selected fromthe class consisting of chlorine and fluorine, it being understood thatat least 3 fluorines are always present and n is an integer of from 1 to2.

This application is a division of copending application Ser. No.304,607, filed Aug. 26, 1963, and now US. Patent No. 3,320,299, which isa continuation-in-part of application Ser. No. 191,432 filed May 1,1962, now abandoned.

The present invention encompasses a new class of compounds which werediscovered as the reaction product re.- sulting from the chemicalcombination of a nitrogenous organic base of the guanidine type with afully halogenated acetone in which the halogen atoms are fluorine or acombination of fluorine and chlorine and at least 3 fluorine atoms arepresent in the fully halogenated ketone. Although their structure hasnot yet been fully elucidated, the compounds are apparently molecularaddition complexes wherein the proportion of organic base to halogenatedacetone is in the ratio of small whole numbers. Pointing toward theaforesaid structural hypothesis is the fact that the formation of thecompounds has never been observed to be accompanied by secondaryproducts as is characteristic of metathetical and substitutionreactions. That the addition complexes are distinct entities having adefinite chemical composition is supported by the consistent analyticaldata and sharp melting points of the purified products.

Accordingly, the new chemical entities of the present invention can beformalistically depicted as follows:

CXa

"ice

wherein each of the substituents R, R R R and R represents hydrogen; analkyl radical of from 1 to 20 carbon atoms, e.g. methyl, ethyl,n-propyl, isobutyl, npentyl, isohexyl, n-hexyl, n-heptyl, sec.-octyl,nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,heptadecyl, octadecyl, and the like; a cycloalkyl radical e.g.cyclopentyl, cyclohexyl, etc.; a benzyl radical; a phenethyl radical; anaryl radical of the benzene and naphthylene series; said radicals havingsuch optional substituents as chlorine, bromine, fluorine, lower alkyl,lower alkoxyl, lower dialkylamino,

-NH NHgC; NH2C; NHz-C and CN H II NH and the like, it being providedthat the number of nonhydrocarbon substituents attached to the samenitrogen atom does not exceed 1, X and X are halogen atoms asrepresented by chlorine and fluorine there always being at least 3fluorine atoms present and n is an integer of from 1 to 2.

Structures falling within the ambit of the general formula include theaddition complexes of completely halogenated acetone with variousguanidine derivatives as below set forth. The invention is moreoverillustrated by the examples which are described elsewhere herein.

Compound 3 ow -W NH 3 Compound 4 Compound 5 Compound 6 Compound 13NH-ji-NH-fiJ-NH,

Compound 14 NHCNH-C-NH ll it rti- R2 1? R4 R wherein R, R R R and R havethe values as above defined. The reaction is conveniently carried. outin the presence of a normally liquid organic solvent of which suitableexamples are the lower saturated water soluble alcohols and ketones,e.g. methanol, ethanol, n-propanol, acetone, methyl ethyl ketone and thelike. In some instances the guanidine component is obtained or purchasedin the form of its salts, i.e. carbonate, hydrochloride, etc., in whichcase the free base can be conveniently generated in situ by treating theguanidine salt with an alkali such as an alkali metal hydroxide or loweralkoxide.

It has been our experience that the reactants combine in simple molarproportions, the ratio of which is that of small whole numbers, therebeing at least one molecule of completely halogenated acetone permolecule of the guanidine reactant. In this connection, the number ofguanyl radicals in the guanidine appears to be a significant factorsince at least one guanyl group is required to bind one molecule of thehalogenated acetone whereas two guanyl radicals per guanidine, e.g. abiguanide derivative, are necessary in order to bind two moles ofhalogenated acetone. However, it does not necessarily follow thataddition complexes of polyguanylguanidines are formed having a pluralityof halogenated moieties since initial introduction of halogenated ketonemay sufficiently deactivate any remaining guanyl groups therebyprecluding further complex formation.

As previously pointed out, the addition complexes of this inventionexhibit fungicidal properties and can therefore be utilized as theactive component or toxicant in the formulation of biocidal compositionsand are particularly effective in combating fungi of the type thatinfect plants. In this connection, the compounds have proven highlyeffective against bean rust, giving 100% protection in many instanceswhen applied to bean plants at a concentration in the order of only afew p.p.m. Moreover, the toxicants did not cause any significantphytotoxic damage to the host plant.

Another extremely useful and unexpected asset of the herein contemplatedaddition complexes is their systemic toxicity, a feature which furtherincreases the utility and versatility of the compounds. As those skilledin the art are aware, a systemic biocide is taken up internally by theorganism to which it is applied and lodges in the living tissues whilestill retaining toxicological properties. When used to protect plantssuch as food crops systemic toxicants have the advantage of not beingsubject to weathering or wash off by raid since they are confined withinthe interstices of the plant tissues which are thus internally immunizedagainst the attack of fungi and similar harmful microorganisms.

In carrying out systemic fungicidal tests, 60 ml. of a solutioncontaining the compound undergoing evaluation is diluted to 50 ppm. andthen placed in small tubes. A pinto bean plant is inserted in each tubeusing a cotton plug to support the seedling and also to retardevaporation. After 48 hours, two plants are inoculated with bean rust.Comparison between the treated and untreated plants is then made and theresults evaluated. In these tests, the compound of Example 2, a typicalrepresentative g ve 190% control at a concentration of 0.75

ppm. which was the lowest concentration tested. Manifestly, thiscompound exhibits an unusually high degree of systemic fungicidalactivity.

Preparations suitable for fungicide applications may be prepared in theform of dusts or sprays. The completely halogenated acetone guanidinecomplex may be combined with a finely divided solid carrier of whichtalc, diatomaceous earth, pyrophyllite, hydrated silica, clay andbentonite are typical examples. In preparing dusts, the active componentnormally comprises about 1 to 15% of the total mixture. Moreover, it isa common practice to employ wetting agents to facilitate dispersing theactive material when the dusts are added to water. Typically, a wettablepowder comprises 20 to 50% of the toxicant, 45 to-75% of one of theaforementioned finely divided solids, 1 to 5% of wetting agent, and 1 to3% of a dispersing agent. Exemplary wetting agents are the sodiumalkylbenzenesulfonates, sodium dodecyl sulfate, and the non-ionicpolyethers as exemplified by the alkylphenoxypolyethoxyethanols. In use,the wettable powder is stirred up in water and the resultant liquidsprayed on plants for protection against fungus diseases. Another commonprocedure for incorporating the toxicants of the invention in a formsuitable for application to plants consists in dissolving the componentin an organic solvent such as xylene, toluene, ethylene dichloridefollowed by emulsifying the resulting solution in water in the presenceof a dispersing agent.

For specific instructions and directions in preparing the aforementionedcomplexes, reference is now made to the following examples which areinserted only for the purpose of illustrating the invention. It will beappreciatedby those having skill in the art to which the inventionpertains that various ramifications and modifications can be effectedWithout departing from the spirit and scope thereof.

EXAMPLE 1 19.7 (0.1 mole) of phenylguanidine carbonate was suspended in50 ml. of alcohol and the free base was liberated by adding to themixture a solution of 2.3 g. of sodium in 70 ml. of absolute alcohol.The reaction was exothermic which may necessitate outside cooling. Afterstirring for 1 hour at room temperature, 19.9 g. (0.1 mole) ofsym-dichlorotetrafluoroacetone was added while maintaining vigorousagitation. After 10 minutes the reaction mixture was filtered and thefiltrate concentrated in vacuo, leaving a syrupy residue. The crudeproduct was dissolved in 50 ml. of benzene and the organic solutionwashed several times with water. A white solid precipitates out and wasfiltered off and dried. The white product, which weighed 27 g., meltedat C. with decomposition and the chemical analysis was in conformitywith the above depicted structure.

The guanidines used as intermediates in this and the following examplesare in most instances known compounds. In general, they can be preparedby reacting a thiourea component with an alkalating agent to form athiouronium salt which is treated with an organic amine having, at leastone hydrogen attached to the nitrogen atom and isolating the resultingguanidine derivative. For further details and specific instructions onthe preparation of the guanidine intermediates, reference is made to thevarious technical and chemical literature sources.

EXAMPLE 2 OClFa 15.0 g. of dodecylguanidine acetate was placed in areaction flask equipped with a stirrer, thermometer and dropping funnelfrom which was'added a solution of 2.9

g. of sodium methoxide in 70 ml. of absolute alcohol, After the additionwas completed, the reaction was stirred for minutes at room temperaturefollowed by the introduction of 11.0 g. of monochloropentafluoroacetonethe addition of which caused a temperature rise 10.6 g. ofdiphenylguanidine was suspended in ml. of methylene dichloride and tothe resulting suspension was introduced 10.0 g. ofchloropentafiuoroacetone. After the introduction of the halogenatedacetone was completed and the mildly exothermic reaction had sub- 5 toC. After assuming room temperature, the reaction sided, the precipitatedreactlon product was separated mixture was poured into 250 ml. of waterand after from the reaction media and isolated as a white solid.standing about 1 hour at room temperature a whlte The melting point was138 c. and the yield amounted precipitate had formed. The solid wasremoved by filtrat 195 g, tion and dried in the open air. The yieldamounted to 10 Using h procedure as given in Example 1 complexes and thePurified mammal melted at Chemlof completely halogenated acetone wereprepared from cal and instrumental analysis were in consonance with theguanidines listed below. It is to be noted that in the above gwenstructure- Example 11a 2 molecules of the halogenated acetone EXAMPLE 3were reacted with one molecule of the guanidine comfi Con," 15 ponent,which, it will be observed, has two guanyl radill 4 02115. As previouslyexplained, polyguanyl guanldlnes may NH C NH Q react with more than onemolecule of the halogenated CF! acetone.

Acetone A Guanidine component component 1 Characterization Example No.:

IFIH 4 C12I'I25NH--CNH2 4FK White solid.

lTIH 5 NH-CNH 4FK White solid, M.P.=134 (D).

IfiIH 151B 6 @NHC-NH-C-Nflz 4FK White solid, M.P.=118 (D).

7 NH-CNH 4FK Yellow glassy, M.P.=70 soli NH 8 NHz-lj-NH-NH: 4FK Whitesolid, M.P.= 0.

NH l o NHz-QI-NH-CN 4FK White solid, M.P.= c.

, I l0 -NHO-NH2C11HCOOH 4FK Brown oil, ND25=1.4758.

R R 11 NH C-NHCNHz 4FK White Solid.

l V CH2 I 1x111 II\IIH 11a 'NHCNHCNH 4FK Yellowlsh viscous 011.

, II 12 NHCNH s p l. I 4FK White Solid, M.P.=95 0.

NH, (IT l3 NHzP3-NHCNH2 4KF I White solid, M.P.=113 0.

CH3 II-|IH 14 CH -NH CNHQNH2 4m: Yellow oil, ND =1.42o5.

CH3 I I IIIH 15.. C12H25NHO'-NH2 3FK White solid, M.P.=119.

Acetone component Characterization Guanidine component Example No.1

IIIH 16 CnHgNH-C-NH2 ITIH v 6FK White solid, M.P. =63.

BFK Yellow Solid, M.P.=130133.

1. A method of inhibiting the growth of fungi which comprises applyingthereto a small but effective amount of a guanidine complex of acompletely halogenated acetone having the formula:

II s NH and -CN; the number of non-hydrocarbon R groups attached to thesame nitrogen atom does not exceed 1; X and X are selected from thegroup consisting of chlorine and fluorine, there always being at leastthree (3) fluorines present, and n is an integer of from 1 to 2.

2. The method of claim 1 wherein said guanidine complex has the formula:

3. The method of claim 1 wherein said guanidine complex has the formula:

4. The method of claim 1 wherein said guanidine complex has the formula:

5. The method of claim 1 wherein said guanidine complex has the formula:

6. The method of claim 1 wherein said guanidine complex has the formula:I

7. The method of claim 1 wherein said guanidine complex has the formula:

NHGNH-NH O O=C(CF301)2 8. The method of claim 1 comprising guanidinecomplex has the formula:

9. The method of claim 1 wherein said guanidine complex has the formula:

10. The method of claim 1 wherein said guanidine complex has theformula:

11. The method of claim 1 wherein said guanidine complex has theformula:

12. The method of claim 1 wherein said guanidine complex has theformula:

13. The method of claim 1 wherein said guanidine complex has theformula:

14. The method of claim 1 wherein said guanidine complex has theformula:

9 10 15. The method of claim 1 wherein said guanidine com- 18. Themethod of claim 1 wherein said guanidine complex has the formula: plexhas the formula:

16. The method of claim 1 wherein said guanidine complex has theformula: References Cited UNITED STATES PATENTS IR'H /C 01F 2 102,390,597 12/1945 Law et a1. 424--325 C2HQ5NH O 2 2,548,509 4/1951Yowell 424-352 ClzF 17. The method of claim 1 wherein said guanidinecom- ALBERT MEYERS, Primary Examiner F has 3116 formula: D. M. STEPHENS,Assistant Examiner NH cm 13 U.S. C1. X.R.

CnHz5NH-C-NH2 9 C 0

